Metabolic Patterns Research Articles

Targeting NPM1 Epigenetically Promotes Postinfarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism.

Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates the phenotypic transition of macrophages; however, the precise mechanisms governing metabolic reprogramming of cardiac reparative macrophages remain poorly understood. In this study, we investigated the role of NPM1 (nucleophosmin 1) in the metabolic and phenotypic shift of cardiac macrophages in the context of MI and explored the therapeutic effect of targeting NPM1 for ischemic tissue repair. Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI to explore NPM1 expression and its correlation with prognostic indicators. Through RNA sequencing, metabolite profiling, histology, and phenotype analyses, we investigated the role of NPM1 in postinfarct cardiac repair using macrophage-specific NPM1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and phenotype transition of NPM1-deficient cardiac macrophages. The therapeutic efficacy of antisense oligonucleotide and inhibitor targeting NPM1 was then assessed in wild-type mice with MI. NPM1 expression was upregulated in the peripheral blood mononuclear cells from patients with MI that closely correlated with adverse prognostic indicators of MI. Macrophage-specific NPM1 deletion reduced infarct size, promoted angiogenesis, and suppressed tissue fibrosis, in turn improving cardiac function and protecting against adverse cardiac remodeling after MI. Furthermore, NPM1 deficiency boosted the reparative function of cardiac macrophages by shifting macrophage metabolism from the inflammatory glycolytic system to oxygen-driven mitochondrial energy production. The oligomeric NPM1 recruited histone demethylase KDM5b to the promoter of Tsc1 (TSC complex subunit 1), the mTOR (mechanistic target of rapamycin kinase) complex inhibitor, reduced histone H3K4me3 modification, and inhibited TSC1 expression, which then facilitated mTOR-related inflammatory glycolysis and antagonized the reparative function of cardiac macrophages. The in vivo administration of antisense oligonucleotide targeting NPM1 or oligomerization inhibitor NSC348884 substantially ameliorated tissue injury and enhanced cardiac recovery in mice after MI. Our findings uncover the key role of epigenetic factor NPM1 in impeding postinfarction cardiac repair by remodeling metabolism pattern and impairing the reparative function of cardiac macrophages. NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for heart failure after MI.

Uptake, accumulation and metabolism of UV-320 in vegetables and its impact on growth and quality

UV-320 is classified as a Substance of Very High Concern (SVHC) by the European Chemicals Agency and has attracted significant attention due to its presence in the environment. Understanding the uptake, translocation and metabolic patterns of UV-320 in vegetables is essential for assessing their ability to bioaccumulate and potential risks to human health. In this study, we investigated the uptake and translocation of UV-320 in lettuce and radish by hydroponic experiments. The results showed that the root concentration factors (Croot/Csolution, RCF) of lettuce and radish were in the range of 47.9 to 464 mL/g and 194 to 787 mL/g, respectively. The transfer factors (Cshoot/Croot, TF) were observed to be 0.001–0.012 for lettuce and 0.02–0.05 for radish. Additionally, non-targeted screening identified twelve phase I and one phase II metabolites of UV-320 in vegetables, which were confirmed based on their molecular formulas and structures. The metabolic pathways involving oxidation, ketonylation and deamination were proposed in vegetables. Also, we have observed that UV-320 inhibits the growth of vegetables. Meanwhile, we evaluated the health risk of UV-320 in lettuce and radish and found that the consumption of lettuce is relatively safe, while the consumption of radish has a risk of HQ >1 for both adults and children, which should be seriously considered. This study provides valuable insights into the behavior and ecological risks of UV-320 in the environment.

Impacts of behaviour and acclimation of metabolic rate on energetics in sheltered ectotherms: a climate change perspective.

Many ectothermic organisms counter harsh abiotic conditions by seeking refuge in underground retreats. Variations in soil hydrothermal properties within these retreats may impact their energy budget, survival and population dynamics. This makes retreat site choice a critical yet understudied component of their strategies for coping with climate change. We used a mechanistic modelling approach to explore the implications of behavioural adjustments and seasonal acclimation of metabolic rate on retreat depth and the energy budget of ectotherms, considering both current and future climate conditions. We used a temperate amphibian, the alpine newt (Ichthyosaura alpestris), as a model species. Our simulations predict an interactive influence of different thermo- and hydroregulatory strategies on the vertical positioning of individuals in underground refuges. The adoption of a particular strategy largely determines the impact of climate change on retreat site choice. Additionally, we found that, given the behavioural thermoregulation/hydroregulation and metabolic acclimation patterns considered, behaviour within the retreat has a greater impact on ectotherm energetics than acclimation of metabolic rate under different climate change scenarios. We conclude that further empirical research aimed at determining ectotherm behavioural strategies during both surface activity and inactivity is needed to understand their population dynamics and species viability under climate change.

MX1 and UBE2L6 are potential metaflammation gene targets in both diabetes and atherosclerosis.

The coexistence of diabetes mellitus (DM) and atherosclerosis (AS) is widespread, although the explicit metabolism and metabolism-associated molecular patterns (MAMPs) responsible for the correlation are still unclear. Twenty-four genetically wild-type male Ba-Ma mini pigs were randomly divided into five groups distinguished by different combinations of 90 mg/kg streptozotocin (STZ) intravenous injection and high-cholesterol/lipid (HC) or high-lipid (HL) diet feeding for 9 months in total. Pigs in the STZ+HC and STZ+HL groups were injected with STZ first and then fed the HC or HL diet for 9 months. In contrast, pigs in the HC+STZ and HL+STZ groups were fed the HC or HL diet for 9 months and injected with STZ at 3 months. The controls were only fed a regular diet for 9 months. The blood glucose and abdominal aortic plaque observed through oil red O staining were used as evaluation indicators for successful modelling of DM and AS. A microarray gene expression analysis of all subjects was performed. Atherosclerotic lesions were observed only in the HC+STZ and STZ+HC groups. A total of 103 differentially expressed genes (DEGs) were identified as common between them. The most significantly enriched pathways of 103 common DEGs were influenza A, hepatitis C, and measles. The global and internal protein-protein interaction (PPI) networks of the 103 common DEGs consisted of 648 and 14 nodes, respectively. The top 10 hub proteins, namely, ISG15, IRG6, IRF7, IFIT3, MX1, UBE2L6, DDX58, IFIT2, USP18, and IFI44L, drive aspects of DM and AS. MX1 and UBE2L6 were the intersection of internal and global PPI networks. The expression of MX1 and UBE2L6 was 507.22 ± 342.56 and 96.99 ± 49.92 in the HC+STZ group, respectively, which was significantly higher than others and may be linked to the severity of hyperglycaemia-related atherosclerosis. Further PPI network analysis of calcium/micronutrients, including MX1 and UBE2L6, consisted of 58 and 18 nodes, respectively. The most significantly enriched KEGG pathways were glutathione metabolism, pyrimidine metabolism, purine metabolism, and metabolic pathways. The global and internal PPI network of the 103 common DEGs consisted of 648 and 14 nodes, respectively. The intersection of the nodes of internal and global PPI networks was MX1 and UBE2L6, suggesting their key role in the comorbidity mechanism of DM and AS. This inference was partly verified by the overexpression of MX1 and UBE2L6 in the HC+STZ group but not others. Further calcium- and micronutrient-related enriched KEGG pathway analysis supported that MX1 and UBE2L6 may affect the inflammatory response through micronutrient metabolic pathways, conceptually named metaflammation. Collectively, MX1 and UBE2L6 may be potential common biomarkers for DM and AS that may reveal metaflammatory aspects of the pathological process, although proper validation is still needed to determine their contribution to the detailed mechanism.

Steroid Metabolomic Signature in Term and Preterm Infants.

Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C19-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born (≥37 weeks gestational age), 42 preterm (30-36 weeks) and 51 early preterm (<30 weeks) infants 38 steroid metabolites were quantified by GC-MS in 24-h urinary samples. In each gestational age group, three distinctive cluster were identified by pattern analysis (k-means clustering). Individual steroidal fingerprints and clinical phenotype were analyzed at the 3rd day of life. Overall, the excretion rates of C21-steroids (glucocorticoid precursors, cortisol, and cortisone metabolites) were low (<99 μg/kg body weight/d) whereas the excretion rates of C19-steroids were up to 10 times higher. There was a shift to higher excretion rates of C19-steroids in both preterm groups compared to term infants but only minor differences in the distribution of C21-steroids. Comparable metabolic patterns were found between gestational age groups: Cluster 1 showed mild elevation of C21- and C19-steroids with the highest incidence of neonatal morbidities in term and severe intraventricular hemorrhage in early preterm infants. In cluster 2 lowest excretion in general was noted but no clinically unique phenotype. Cluster 3 showed highest elevation of C21-steroids and C19-steroids but no clinically unique phenotype. Significant differences in steroid metabolism between clusters are only partly reflected by gestational age and disease severity. In early preterm infants, higher excretion rates of glucocorticoids and their precursors were associated with severe cerebral hemorrhage. High excretion rates of C19-steroids in preterm infants may indicate a biological significance.

Important nutrient sources and carbohydrate metabolism patterns in the growth and development of spargana

BackgroundSparganosis is a worldwide food-borne parasitic disease caused by spargana infection, which infects the muscle of frogs and snakes as well as many tissues and organs in humans. There are currently no viable treatments for sparganosis. Understanding spargana’s nutrition source and carbohydrate metabolism may be crucial for identifying its energy supply and establishing methods of treatment for sparganosis.MethodsUsing an amino acid analyzer and nutrient concentration detection kits, we assessed nutrient concentrations in the muscles of Fejervarya limnocharis and Pelophylax plancyi infected or not infected with spargana. Quantitative polymerase chain reaction (PCR) was used to quantify the major enzymes involved in five glucose metabolism pathways of spargana developing in vivo. We also used quantitative PCR to assess key enzymes and transcriptome sequencing to explore the regulation of carbohydrate metabolic pathways in vitro in response to different 24-h food treatments.ResultsInfected muscle tissues had considerably higher concentrations of glucogenic and/or ketogenic amino acids, glucose, and glycogen than non-infected muscle tissues. We discovered that the number of differentially expressed genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was larger in low-glucose than in other dietary groups. We examined differences in the expression of genes producing amino acid transporters, glucose transporters, and cathepsins in spargana grown in various nutritional environments. In the normal saline group, only the major enzymes in the tricarboxylic acid cycle (TCA), glycogenesis, and glycogenolysis pathways were expressed. The l-glutamine group had the greatest transcriptional levels of critical rate-limiting enzymes of gluconeogenesis and glycogenesis. Furthermore, the low-glucose group had the highest transcriptional levels of critical rate-limiting enzymes involved in the TCA, glycolytic, and glycogenolysis pathways. Surprisingly, when compared to the in vitro culturing groups, spargana developing in vivo exhibited higher expression of these critical rate-limiting enzymes in these pathways, with the exception of the pentose phosphate pathway.ConclusionsSpargana have a variety of nutritional sources, and there is a close relationship between nutrients and the carbohydrate metabolism pathways. It takes a multi-site approach to block nutrient absorption and carbohydrate metabolism pathways to provide energy to kill them.Graphical

Is the Pyrenean newt (&lt;em&gt;Calotriton asper&lt;/em&gt;) a thermoconformer? Cloacal and water temperature in two different thermal periods in a Pre-Pyrenean stream population

In ectothermic animals, heat seems to be a determining factor because it influences many vital activities such as locomotion, the ability to escape, feeding, and reproduction, among others. In aquatic environments, physical characteristics of water prevent small ectotherms from thermoregulating and therefore it is expected that their body temperature remains similar to water temperature. Throughout its distribution and annual cycle, the Pyrenean newt (Calotriton asper) is exposed to a wide range of water temperatures that affect its biological and ecological traits like the standard metabolic rate, oxygen consumption, activity period and growth pattern. This study analyses the relationship between the cloacal and water temperatures in a Pre-Pyrenean population of C. asper in two periods with well differentiated water temperatures (July and September). The aims are to establish if there are differences between sexes in cloacal temperature, whether reproductive activity modifies cloacal temperature, and to analyse the degree of thermoconformity of the species. The results indicate that cloacal temperature depends on the water temperature, corroborating the idea that C. asper is mainly a thermoconformer, as it corresponds to an aquatic ectotherm. However, the cloacal temperature of newts was slightly higher than water temperature. In individuals in amplexus, cloacal temperature was significantly higher than in specimens that are not in this mating position, and in July, females showed much greater dispersion in cloacal temperature than males, which is probably related to spawning behaviour.

Clinical features, disease progression, and nuclear imaging in ATXN2-related parkinsonism in a longitudinal cohort.

Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD.

Circulating metabolome landscape in Lynch syndrome.

Circulating metabolites systemically reflect cellular processes and can modulate the tissue microenvironment in complex ways, potentially impacting cancer initiation processes. Genetic background increases cancer risk in individuals with Lynch syndrome; however, not all carriers develop cancer. Various lifestyle factors can influence Lynch syndrome cancer risk, and lifestyle choices actively shape systemic metabolism, with circulating metabolites potentially serving as the mechanical link between lifestyle and cancer risk. This study aims to characterize the circulating metabolome of Lynch syndrome carriers, shedding light on the energy metabolism status in this cancer predisposition syndrome.This study consists of a three-group cross-sectional analysis to compare the circulating metabolome of cancer-free Lynch syndrome carriers, sporadic colorectal cancer (CRC) patients, and healthy non-carrier controls. We detected elevated levels of circulating cholesterol, lipids, and lipoproteins in LS carriers. Furthermore, we unveiled that Lynch syndrome carriers and CRC patients displayed similar alterations compared to healthy non-carriers in circulating amino acid and ketone body profiles. Overall, cancer-free Lynch syndrome carriers showed a unique circulating metabolome landscape.This study provides valuable insights into the systemic metabolic landscape of Lynch syndrome individuals. The findings hint at shared metabolic patterns between cancer-free Lynch syndrome carriers and CRC patients.

Screening, Diagnosis, and Treatment of Patients with Binge Eating Disorder and Obesity: What the Endocrinologist Needs to Know

Binge eating disorder (BED) is the most common eating disorder categorized in the DSM-V, but it is often not diagnosed in patients with obesity because it can be difficult to detect in these patients who often have altered eating patterns. In this narrative review, we have highlighted the most recent findings in the screening, diagnosis, and treatment of patients with BED and obesity. The results of our search showed that many BED patients are not obese, and most people with obesity do not have binge behavior. In the diagnostic assessment of these patients, it is important to evaluate not only the clinical and nutritional status and the presence of medical comorbidities, but also the psychological signs and symptoms related to psychiatric comorbidities to define the appropriate diagnosis and the consequent level of treatment. Well-tolerated drugs with action on both body weight and binges can be useful as a second-line complement to cognitive behavioral therapy (CBT). Specific guidelines are needed to obtain consensus on appropriate recommendations in patients with obesity and BED approaching bariatric surgery, taking into account not only weight reduction and clinical data, but also eating behaviors. Identification of BED is important for targeting individuals at high risk of obesity, adverse metabolic patterns, and cardiovascular disease. The challenge is to also achieve lasting weight loss in patients with BED and concomitant obesity.

Model-guided metabolic rewiring to bypass pyruvate oxidation for pyruvate derivative synthesis by minimizing carbon loss.

Engineering microbial hosts to synthesize pyruvate derivatives depends on blocking pyruvate oxidation, thereby causing severe growth defects in aerobic glucose-based bioprocesses. To decouple pyruvate metabolism from cell growth to improve pyruvate availability, a genome-scale metabolic model combined with constraint-based flux balance analysis, geometric flux balance analysis, and flux variable analysis was used to identify genetic targets for strain design. Using translation elements from a ~3,000 cistronic library to modulate fxpK expression in a bicistronic cassette, a bifido shunt pathway was introduced to generate three molecules of non-pyruvate-derived acetyl-CoA from one molecule of glucose, bypassing pyruvate oxidation and carbon dioxide generation. The dynamic control of flux distribution by T7 RNAP-mediated synthetic small RNA decoupled pyruvate catabolism from cell growth. Adaptive laboratory evolution and multi-omics analysis revealed that a mutated isocitrate dehydrogenase functioned as a metabolic switch to activate the glyoxylate shunt as the only C4 anaplerotic pathway to generate malate from two molecules of acetyl-CoA input and bypass two decarboxylation reactions in the tricarboxylic acid cycle. A chassis strain for pyruvate derivative synthesis was constructed to reduce carbon loss by using the glyoxylate shunt as the only C4 anaplerotic pathway and the bifido shunt as a non-pyruvate-derived acetyl-CoA synthetic pathway and produced 22.46, 27.62, and 6.28 g/L of l-leucine, l-alanine, and l-valine by a controlled small RNA switch, respectively. Our study establishes a novel metabolic pattern of glucose-grown bacteria to minimize carbon loss under aerobic conditions and provides valuable insights into cell design for manufacturing pyruvate-derived products.IMPORTANCEBio-manufacturing from biomass-derived carbon sources using microbes as a cell factory provides an eco-friendly alternative to petrochemical-based processes. Pyruvate serves as a crucial building block for the biosynthesis of industrial chemicals; however, it is different to improve pyruvate availability in vivo due to the coupling of pyruvate-derived acetyl-CoA with microbial growth and energy metabolism via the oxidative tricarboxylic acid cycle. A genome-scale metabolic model combined with three algorithm analyses was used for strain design. Carbon metabolism was reprogrammed using two genetic control tools to fine-tune gene expression. Adaptive laboratory evolution and multi-omics analysis screened the growth-related regulatory targets beyond rational design. A novel metabolic pattern of glucose-grown bacteria is established to maintain growth fitness and minimize carbon loss under aerobic conditions for the synthesis of pyruvate-derived products. This study provides valuable insights into the design of a microbial cell factory for synthetic biology to produce industrial bio-products of interest.

Metabolic Patterns of Flavonoid and Its Key Gene Expression Characteristics of Five Cultivars of Tulipa gesneriana during Flower Development

Flower color is one of the most important ornamental traits of tulips (Tulipa gesneriana). Five typical tulip cultivars were selected to identify the flavonoid components and analyze their key gene expression in their tepals. Firstly, after preliminary determination of the pigment type, the flavonoids were identified by UPLC-Q-TOF-MS. A total of 17 anthoxanthins were detected in the five cultivars. The total anthoxanthin content in the white tulip and the red tulip showed a similar decreasing trend, while an increasing trend was observed in the black tulip. Similarly, a total of 13 anthocyanins were detected in five tulip cultivars. The black tulip contained the largest number of anthocyanins, mainly delphinidin derivatives (Dp) and cyanidin derivatives (Cy). The total anthocyanin content (TAC) in the orange, red, and black cultivars was higher than that in the white and yellow cultivars and presented an overall increase trend along with the flower development. TgCHS, TgFLS, TgF3H, TgF3′H, TgF3′5′H, and TgDFR, as key structural genes, were involved in the flavonoid synthesis pathway, and the expression patterns of these genes are basically consistent with the components and accumulation patterns of flavonoids mentioned above. Taken together, the flower color in tulips was closely related to the composition and content of anthocyanins and anthoxanthins, which were indeed regulated by certain key structural genes in the flavonoid pathway.

Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson's Disease.

Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.

Comparative Analysis of the Gelsemium Alkaloids Metabolism in Human, Pig, Goat, and Rat Liver Microsomes.

The aim of this study was to investigate the metabolism of Gelsemium elegans in human, pig, goat and rat liver microsomes and to elucidate the metabolic pathways and cleavage patterns of the Gelsemium alkaloids among different species. A human, goat, pig and rat liver microsomes were incubated in vitro. After incubating at 37°C for 1 hour and centrifuging, the processed samples were detected by HPLC/Qq-TOFMS was used to detect alcohol extract of Gelsemium elegans and its metabolites. Forty-six natural products were characterized from alcohol extract of Gelsemium elegans and 13 metabolites were identified. These 13 metabolites belong to the gelsemine, koumine, gelsedine, humantenine, yohimbane, and sarpagine classes of alkaloids. The metabolic pathways included oxidation, demethylation and dehydrogenation. After preliminary identification, the metabolites detected in the four species were different. All 13 metabolites were detected in pig and rat microsomes, but no oxidative metabolites of Gelsedine-type alkaloids were detected in goat and human microsomes. In this study, Gelsemium elegans metabolic patterns in different species are clarified and the in vitro metabolism of Gelsemium elegans is investigated. It is of great significance for its clinical development and rational application.

Topographic metabolism-function relationships in Alzheimer's disease: A simultaneous PET/MRI study.

Disruptions of neural metabolism and function occur in parallel during Alzheimer's disease (AD). While many studies have shown diverse metabolic-functional relationships in specific brain regions, much less is known about how large-scale network-level functional activity is associated with the topology of metabolism in AD. In this study, we took the advantages of simultaneous PET/MRI and multivariate analyses to investigate the associations between AD-related stereotypical spatial patterns (topographies) of glucose metabolism, measured by fluorodeoxyglucose PET, and functional connectivity, measured by resting-state functional MRI. A total of 101 participants, including 37 patients with AD, 25 patients with mild cognitive impairment (MCI), and 39 cognitively normal controls, underwent PET/MRI scans and cognitive assessments. Three pairs of distinct but optimally correlated metabolic and functional topographies were identified, encompassing large-scale networks including the default-mode, executive and control, salience, attention, and subcortical networks. Importantly, the metabolic-functional associations were not only limited to one-to-one-corresponding regions, but also occur in remote and non-overlapping regions. Furthermore, both glucose metabolism and functional connectivity, as well as their linkages, exhibited various degrees of disruptions in patients with MCI and AD, and were correlated with cognitive decline. In conclusion, our results support distributed and heterogeneous topographic associations between metabolism and function, which are jeopardized by AD. Findings of this study may deepen our understanding of the pathological mechanism of AD through the perspectives of both local energy efficiency and long-term interactions between synaptic disruption and functional disconnection contributing to the clinical symptomatology in AD.

Metabolomics and transcriptomics of embryonic livers reveal hypoxia adaptation of Tibetan chickens

BackgroundExploring the hypoxia adaptation mechanism of Tibetan chicken is of great significance for revealing the survival law of Tibetan chicken and plateau animal husbandry production. To investigate the hypoxia adaptation of Tibetan chickens (TBCs), an integrative metabolomic-transcriptomic analysis of the liver on day 18 of embryonic development was performed. Dwarf laying chickens (DLCs), a lowland breed, were used as a control.ResultsA total of 1,908 metabolites were identified in both TBCs and DLCs. Energy metabolism and amino acid metabolism related differentially regulated metabolites (DRMs) were significantly enriched under hypoxia. Important metabolic pathways including the TCA cycle and arginine and proline metabolism were screened; PCK1, SUCLA2, and CPS1 were found to be altered under hypoxic conditions. In addition, integrated analysis suggested potential differences in mitochondrial function, which may play a crucial role in the study of chicken oxygen adaptation.ConclusionsThese results suggest that hypoxia changed the gene expression and metabolic patterns of embryonic liver of TBCs compared to DLCs. Our study provides a basis for uncovering the molecular regulation mechanisms of hypoxia adaptation in TBCs with the potential application of hypoxia adaptation research for other animals living on the Qinghai-Tibet plateau, and may even contribute to the study of diseases caused by hypoxia.

Dominance of net autotrophy in arid landscape low relief polar lakes, Nunavut, Canada.

The Arctic is the fastest warming biome on the planet, and environmental changes are having striking effects on freshwater ecosystems that may impact the regional carbon cycle. The metabolic state of Arctic lakes is often considered net heterotrophic, due to an assumed supply of allochthonous organic matter that supports ecosystem respiration and carbon mineralization in excess of rates of primary production. However, lake metabolic patterns vary according to regional climatic characteristics, hydrological connectivity, organic matter sources and intrinsic lake properties, and the metabolism of most Arctic lakes is unknown. We sampled 35 waterbodies along a connectivity gradient from headwater to downstream lakes, on southern Victoria Island, Nunavut, in an area characterized by low precipitation, organic-poor soils, and high evaporation rates. We evaluated whether lakes were net autotrophic or heterotrophic during the open water period using an oxygen isotopic mass balance approach. Most of the waterbodies were autotrophic and sites of net organic matter production or close to metabolic equilibrium. Autotrophy was associated with higher benthic primary production, as compared to its pelagic counterpart, due to the high irradiance reaching the bottom and efficient internal carbon and nutrient cycling. Highly connected midstream and downstream lakes showed efficient organic matter cycling, as evidenced by the strong coupling between gross primary production (GPP) and ecosystem respiration, while decoupling was observed in some headwater lakes with significantly higher GPP. The shallow nature of lakes in the flat, arid region of southern Victoria Island supports net autotrophy in most lakes during the open water season. Ongoing climate changes that lengthen the ice-free irradiance period and increase rates of nutrient evapoconcentration may further promote net autotrophy, with uncertain long-term effects for lake functioning.

Chemical Epigenetic Regulation Secondary Metabolites Derived from Aspergillus sydowii DL1045 with Inhibitory Activities for Protein Tyrosine Phosphatases.

Protein tyrosine phosphatases (PTPs) are ubiquitous in living organisms and are promising drug targets for cancer, diabetes/obesity, and autoimmune disorders. In this study, a histone deacetylase inhibitor called suberoylanilide hydroxamic acid (SAHA) was added to a culture of marine fungi (Aspergillus sydowii DL1045) to identify potential drug candidates related to PTP inhibition. Then, the profile of the induced metabolites was characterized using an integrated metabolomics strategy. In total, 46% of the total SMs were regulated secondary metabolites (SMs), among which 20 newly biosynthesized metabolites (10% of the total SMs) were identified only in chemical epigenetic regulation (CER) broth. One was identified as a novel compound, and fourteen compounds were identified from Aspergillus sydowii first. SAHA derivatives were also biotransformed by A. sydowii DL1045, and five of these derivatives were identified. Based on the bioassay, some of the newly synthesized metabolites exhibited inhibitory effects on PTPs. The novel compound sydowimide A (A11) inhibited Src homology region 2 domain-containing phosphatase-1 (SHP1), T-cell protein tyrosine phosphatase (TCPTP) and leukocyte common antigen (CD45), with IC50 values of 1.5, 2.4 and 18.83 μM, respectively. Diorcinol (A3) displayed the strongest inhibitory effect on SHP1, with an IC50 value of 0.96 μM. The structure-activity relationship analysis and docking studies of A3 analogs indicated that the substitution of the carboxyl group reduced the activity of A3. Research has demonstrated that CER positively impacts changes in the secondary metabolic patterns of A. sydowii DL1045. The compounds produced through this approach will provide valuable insights for the creation and advancement of novel drug candidates related to PTP inhibition.

Long-Range Epitaxial MOF Electronics for Continuous Monitoring of Human Breath Ammonia.

As an important biomarker, ammonia exhibits a strong correlation with protein metabolism and specific organ dysfunction. Limited by the immobile instrumental structure, invasive and complicated procedures, and unsatisfactory online sensitivity and selectivity, current medical diagnosis fails to monitor this chemical in real time efficiently. Herein, we present the successful synthesis of a long-range epitaxial metal-organic framework on a millimeter domain-sized single-crystalline graphene substrate (LR-epi-MOF). With a perfect 30° epitaxial angle and a mere 2.8% coincidence site lattice mismatch between the MOF and graphene, this long-range-ordered epitaxial structure boosts the charge transfer from ammonia to the MOF and then to graphene, thereby promoting the overall charge delocalization and exhibiting extraordinary electrical global coupling properties. This unique characteristic imparts a remarkable sensitivity of 0.1 ppb toward ammonia. The sub-ppb detecting capability and high anti-interference ability enable continuous information recording of breath ammonia that is strongly correlated with the intriguing human lifestyle. Wearable electronics based on the LR-epi-MOF could accurately portray the active protein metabolism pattern in real time and provide personal assistance in health management.

Developmental energetics in the oviparous corn snake, Pantherophis guttatus, confirms a conservative evolutionary pattern in snakes

Eggs of oviparous reptiles are ideal models for studying evolutionary patterns of embryonic metabolism since they allow tracking of energy allocation during development. Analyzing oxygen consumption of whole eggs throughout development indicates three patterns among reptiles. Embryos initially grow and consume oxygen exponentially, but oxygen consumption slows, or drops before hatching in some species. Turtles, crocodilians, and most lizards follow curves with initial exponential increases followed by declines, whereas embryonic snakes that have been studied exhibit a consistently exponential pattern. This study measured oxygen consumption of corn snake, Pantherophis guttatus, embryos to determine if this species also exhibits an exponential increase in oxygen consumption. Individual eggs, sampled weekly from oviposition to hatching, were placed in respirometry chambers for 24-h during which oxygen consumption was recorded. Embryos were staged and carcasses and yolk were weighed separately. Results indicate steady inclines in oxygen consumption during early stages of development, with a rapid increase prior to hatching. The findings support the hypothesis that embryonic oxygen consumption of snakes differs from most other non-avian reptiles. Total energy required for development was determined based on calorimetry of initial yolk compared to hatchlings and residual yolk and by integration of the area under the curve plotting oxygen consumption versus age of embryos. The cost of development estimates based on these two methods were 6.4 and 10.0 kJ, respectively. Our results emphasize the unique physiological aspects of snake embryogenesis and illustrate how the study of physiological characteristics can contribute to the broader understanding of reptilian evolution.